Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cell Rep. 2013 Dec 26;5(6):1625-38. doi: 10.1016/j.celrep.2013.11.025. Epub 2013 Dec 12.
Defining the role of epigenetic regulators in hematopoiesis has become critically important, because recurrent mutations or aberrant expression of these genes has been identified in both myeloid and lymphoid hematological malignancies. We found that PRMT4, a type I arginine methyltransferase whose function in normal and malignant hematopoiesis is unknown, is overexpressed in acute myelogenous leukemia patient samples. Overexpression of PRMT4 blocks the myeloid differentiation of human stem/progenitor cells (HSPCs), whereas its knockdown is sufficient to induce myeloid differentiation of HSPCs. We demonstrated that PRMT4 represses the expression of miR-223 in HSPCs via the methylation of RUNX1, which triggers the assembly of a multiprotein repressor complex that includes DPF2. As part of the feedback loop, PRMT4 expression is repressed posttranscriptionally by miR-223. Depletion of PRMT4 results in differentiation of myeloid leukemia cells in vitro and their decreased proliferation in vivo. Thus, targeting PRMT4 holds potential as a novel therapy for acute myelogenous leukemia.
定义表观遗传调节剂在造血中的作用变得至关重要，因为这些基因的反复突变或异常表达已在髓系和淋巴造血恶性肿瘤中被发现。我们发现，PRMT4 是一种 I 型精氨酸甲基转移酶，其在正常和恶性造血中的功能尚不清楚，在急性髓系白血病患者样本中过表达。PRMT4 的过表达会阻止人类干细胞/祖细胞（HSPCs）的髓系分化，而其敲低足以诱导 HSPCs 的髓系分化。我们证明，PRMT4 通过 RUNX1 的甲基化来抑制 HSPCs 中 miR-223 的表达，从而触发包括 DPF2 在内的多种蛋白抑制复合物的组装。作为反馈回路的一部分，PRMT4 的表达被 miR-223 转录后抑制。PRMT4 的耗竭导致体外髓系白血病细胞的分化及其体内增殖减少。因此，靶向 PRMT4 作为一种新的急性髓系白血病治疗方法具有潜力。
